The long-term objective of our work is to develop new approaches to control the harmful effects of inflammatory processes (such as those observed in periodontitis), while maintaining the beneficial effects (e.g. tissue repair, resolution of infections). Accurate discrimination between normal and dysregulated inflammatory processes requires a deeper understanding of the regulatory mechanisms affecting gene transcription of pro-inflammatory cytokines such as TNF. The studies we propose here build upon our recent results, in which we identified, cloned, and partially characterized the novel transcription factor LITAF. We have defined a role for LITAF as a positive regulator of TNF expression, and have found that binding of the LITAF regulatory element to the TNF promoter occurs within a region from nucleotides -550 to -487.
The Specific Aims of this proposal are designed to test the twin hypotheses that (1) LITAF regulates TNF gene expression in vivo and (2) that LITAF plays an important role in inflammatory disease. The proposed identification of the minimal and specific DNA sequence responsible for protein binding to LITAF Aim (1a) will allow identification of other promoters that may be targeted by this protein, and permit evaluation of the role of LITAF in the regulation of their respective genes Aim (1d): To accomplish this, we will engineer selected mutations within the human and murine TNF promoters, to reveal the exact DNA binding sequence controlled by LITAF Aim (1b). Coupling of the mutant promoters to reporter genes will allow us to assess whether these mutant promoters fail to be activated by LITAF Aim (1c). Mutant LITAF proteins (muteins) will be designed to identify both the DNA- binding and trans-activation domains (Aim 2), and this information will serve as a powerful tool to elucidate LITAF- promoter interactions in other genes. The creation of LITAF knockout mice will build upon the results of Aims 1 and 2 to evaluate the hypothesis that the LITAF gene product, through its capacity to regulate TNF activity, plays an important role in the development of inflammatory diseases, including periodontitis (Aims 3a and 3b).
Aim 3 c will build upon our recent finding linking LITAF to p53, and will investigate how LITAF could be induced through TLR/TNFR and p53-mediated pathways to help mediate apoptosis. Our discovery of the novel protein LITAF, a factor that helps regulates TNF transcription and possibly apoptosis, will serve as a new tool to dissect the complex mechanisms which mediate TNF expression in various inflammatory conditions, including periodontitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Dental & Craniofacial Research (NIDCR)
Type
Research Project (R01)
Project #
5R01DE014079-03
Application #
6697478
Study Section
Oral Biology and Medicine Subcommittee 1 (OBM)
Program Officer
Lumelsky, Nadya L
Project Start
2002-01-01
Project End
2005-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
3
Fiscal Year
2004
Total Cost
$285,250
Indirect Cost
Name
Boston University
Department
Dentistry
Type
Schools of Dentistry
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
Libby, Peter; Loscalzo, Joseph; Ridker, Paul M et al. (2018) Inflammation, Immunity, and Infection in Atherothrombosis: JACC Review Topic of the Week. J Am Coll Cardiol 72:2071-2081
Singh, Shailendra P; Huck, Olivier; Abraham, Nader G et al. (2018) Kavain Reduces Porphyromonas gingivalis-Induced Adipocyte Inflammation: Role of PGC-1? Signaling. J Immunol 201:1491-1499
Cai, Bin; Panek, James S; Amar, Salomon (2018) Kava analogues as agents for treatment of periodontal diseases: Synthesis and initial biological evaluation. Bioorg Med Chem Lett 28:2667-2669
Alshammari, Abdulsalam; Patel, Jayesh; Al-Hashemi, Jacob et al. (2017) Kava-241 reduced periodontal destruction in a collagen antibody primed Porphyromonas gingivalis model of periodontitis. J Clin Periodontol 44:1123-1132
Huck, Olivier; Al-Hashemi, Jacob; Poidevin, Laetitia et al. (2017) Identification and Characterization of MicroRNA Differentially Expressed in Macrophages Exposed to Porphyromonas gingivalis Infection. Infect Immun 85:
Tang, Xiaoren; Amar, Salomon (2016) Kavain Inhibition of LPS-Induced TNF-? via ERK/LITAF. Toxicol Res (Camb) 5:188-196
Tang, Xiaoren; Amar, Salomon (2016) Kavain Involvement in LPS-Induced Signaling Pathways. J Cell Biochem 117:2272-80
Tang, Xiaoren; Amar, Salomon (2015) p53 suppresses CCL2-induced subcutaneous tumor xenograft. Tumour Biol 36:2801-8
Tang, Xiaoren; Yang, Yu; Yuan, Huaiping et al. (2013) Novel transcriptional regulation of VEGF in inflammatory processes. J Cell Mol Med 17:386-97
Bertolo, Cristina; Roa, Sergio; Sagardoy, Ainara et al. (2013) LITAF, a BCL6 target gene, regulates autophagy in mature B-cell lymphomas. Br J Haematol 162:621-30

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